OVERVIEW: What every practitioner needs to know

Are you sure your patient has viral gastroenteritis? What are the typical findings for this disease?

Clinical Presentation

History

Viral gastroenteritis typically presents with little to no fever along with watery diarrhea. As the virus does not invade the intestinal mucosa, blood and/or mucus in the stool is not expected and, if present, should raise the possibility of bacterial or parasitic etiology for the diarrhea. The biggest concern with viral gastroenteritis is dehydration, so a careful history of the frequency of vomiting and diarrhea, along with the ability to tolerate PO and the urine output is critical. History of daycare attendance, others at home ill and possibly symptoms associated with an outbreak are important clues, as many outbreaks are associated with a viral etiology, particularly norovirus. In addition, to assess the hydration status and severity of the illness, determine recent oral intake, urine output, and any change in mental status.

Rotavirus characteristically begins with vomiting, and fever may be present. Diarrhea may begin in conjunction with the vomiting or a day to two later and may be severe. The combination of the vomiting and the diarrhea is likely what leads to the high rate of dehydration among children with rotavirus. Complete resolution of symptoms typically occurs within seven days. Gastroenteritis associated with norovirus has been shown to be nearly indistinguishable from disease caused by rotavirus, including similarity of age and symptoms. The main distinguishing feature is the more frequent and prolonged fever in children with rotavirus compared with norovirus. Additionally, while norovirus may cause dehydration resulting in hospitalization, the percentage of children developing dehydration from norovirus is much lower than the occurrence in children with rotavirus. The clinical picture of enteric adenovirus is similar to that of rotavirus. In contrast to the nonenteric adenoviruses, high fevers and respiratory symptoms are rare. Disease can be persistent and severe in the immunocompromised host.

Physical Examination

There are no findings of physical examination that are specifically associated with any agent causing viral gastroenteritis. The main purpose of the physical examination in this condition is to assess the level of dehydration as well as look for other findings that may lead to an alternative diagnosis. Validated clinical scoring systems, based on the child's mental status, thirst, pulse rate and character, along with evaluation of the mucous membranes (tears and saliva) and urine output, are available to assess the hydration status of the child. Dehydration should then be categorized as mild (<3% of body weight, moderate (3-10% loss of body weight or severe (>10% loss of body weight), which will guide rehydration therapy.

What other disease/condition shares some of these symptoms?

What caused this disease to develop at this time?

Transmission of viral gastroenteritis is primarily by the fecal-oral route, both through close person-to-person contact and through fomites, as well as possibly by contaminated food and/or water. Frequent hand washing is the most effective measure to decrease fecal-oral transmission. Because the effectiveness of alcohol-based hand sanitizers for norovirus is uncertain, handwashing should be performed with soap and water if norovirus is suspected. Additionally, norovirus is resistant to multiple chemical agents, which requires contaminated surfaces to be cleaned with sodium hypochlorite (bleach) at a minimum concentration of 1,000 ppm.

Rotaviruses and noroviruses both are shed in high concentrations in the stools (>108 organisms per gram of stool) of infected individuals. That, along with the low inoculum needed for infection (perhaps as low as 100 organisms) makes both viruses highly communicable.

Rotavirus

Rotavirus is ubiquitous, with equivalent incidence rates in the developed and developing worlds. This suggests that methods other than hygiene are needed to eliminate the infection. In temperate climates, the infection rates peak between November and April, but cases may occur throughout the year. Introduction of the RV vaccine may be altering the epidemiology of the disease; data for the first two years after introduction of the vaccine in the United States has demonstrated an 11 week and 8 week later onset of disease in 2007-2008 and 2008-2009, respectively, compared with the previous 15 years. Additionally, the length of the season was 12 and 9 weeks shorter (in 2007-2008 and 2008-2009, respectively) compared with previous data. Seasonal variations in incidence are less prominent in tropical climates, but infections tend to be more common during the cooler/drier months. During peak months, before the introduction of the rotavirus vaccine, up to 70% of admissions for non-bacterial gastroenteritis in the United States were due to rotavirus.

Symptoms of rotavirus (see below) begin about 1-3 days after exposure. Illness can range from mild with occasional diarrhea to severe, resulting in significant dehydration and death. In infants, up to 40% of the cases of necrotizing enterocolitis have been associated with rotavirus infection.

While death due to rotavirus in the United States is rare (approximately 40 cases/year), approximately 200,000 Emergency Department visits/year in the United States are due to rotavirus, resulting in up to 50,000 children per year being hospitalized to treat the dehydration caused by the infection. It has been estimated that in excess of $1 billion is spent yearly in the United States to treat rotaviral infections, not counting the cost of parents missing work. Disease severity is inversely related to the age of the child, with most severe cases occurring in the first 3 years of life. Immunity, at least partial, from prior infections in childhood is thought to be why disease severity is usually mild in older children and adults.

Norovirus

Noroviruses are the leading cause of outbreaks of gastroenteritis and an important cause of sporadic gastroenteritis in both children and adults. Over two-thirds of all foodborne gastroenteritis outbreaks are caused by norovirus. It is estimated that more than 23 million cases of norovirus gastroenteritis occur yearly in the United States. Most sporadic disease caused by norovirus occurs in children under 4 years of age, possibly due to poor hygiene practices, a partial immunity in older children and adults, or a combination of the two. Outbreaks with norovirus involve people of all ages, and have occurred in a number of settings, including daycare, picnics, cruise ships and nursing homes.

The incubation period usually is 24 to 48 hours. The onset of symptoms is typically manifested by vomiting, which has led the infection to be nicknamed the "winter vomiting illness". Symptoms usually last for 1-2 days followed by total recovery. Symptoms from norovirus infections are typically less severe than rotavirus, resulting in fewer hospitalizations and thus an underappreciation of the frequency of the infection outside the outbreak setting. However, it is estimated that approximately 12% of the cases of children hospitalized for gastroenteritis are caused by norovirus, and about 200,000 children die each year, predominantly in the developing world, of this infection. Sporadic norovirus infections peak in the spring to early summer, about 3-4 months later than the peak of rotavirus. With the introduction of the rotavirus vaccine over the past 4 years, norovirus has become the leading cause of episodic gastroenteritis in children in many areas of the United States. Norovirus may be shed in the stool for up to 8 weeks after infection and is thought to be why secondary cases, especially within the household, are common.

Recently, it has been discovered that human blood group antigens (HBGAs) are highly associated with susceptibility to infection with norovirus. In addition to red blood cells, HBGAs are expressed on intestinal epithelium and are thought to be binding sites for norovirus. People with HBGAs on their intestinal epithelium, termed "secretors," are highly susceptible to infection, while "non-secretors" appear to have a natural immunity to the virus.

Astrovirus

Astrovirus has been associated with both sporadic disease as well as outbreaks of gastroenteritis in daycare centers, schools, and hospitals. Recent reports have noted astrovirus to be associated with up to 10% of the sporadic cases of gastroenteritis in young children, but this may be due to more intense attempts to detect the organism among ill children. As with most other agents associated with viral gastroenteritis, infants and toddlers are at an increased risk of developing an infection with astrovirus. By 5 years of age, over 90% of children have evidence of a previous infection with astrovirus.

Symptoms of astrovirus gastroenteritis typically begin 1 to 4 days after exposure, with illness usually lasting 1 to 4 days. Diarrhea is the most common symptom and may be accompanied by vomiting and occasionally abdominal distention. Dehydration may occur but is uncommon. Whlle the virus is typically shed for approximately 5 days after the onset of symptoms, some people, particularly immunocompromised persons, may shed the virus for weeks despite being asymptomatic.

Enteric Adenovirus

The enteric adenovirus principally causes symptomatic disease in children under 4 years of age, with cases reported throughout the year. Viral shedding may last for weeks but is highest during the first few days of illness; it is during this time that the virus is the most communicable. Adenoviruses are unusually stable to chemical and physical agents and to adverse pH conditions, thus allowing for prolonged survival outside the body.

Viral gastroenteritis is one of the most common infections in children in both the developed and developing world. Many viruses have been associated with gastroenteritis but four—rotavirus, norovirus, enteric adenovirus, and astrovirus—cause the vast majority of disease. While most cases of viral gastroenteritis in the United States are mild, over 500,000 children worldwide die yearly from viral gastroenteritis, primarily due to rotavirus and norovirus.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory

As there are no historical or physical findings pathognomonic for a specific agent causing viral gastroenteritis, definitive diagnosis requires laboratory confirmation. But, since a specific diagnosis will not alter the primary therapy, neither the Centers for Disease Control and Prevention (CDC) nor the American Academy of Pediatrics (AAP) recommend laboratory testing to determine the etiology of uncomplicated acute gastroenteritis with mild or moderate dehydration.

Electron microscopy may be used for the diagnosis of viral gastroenteritis. While this method is used in public health laboratories in many countries; it requires a highly qualified microscopist and very expensive equipment, making epidemiological or clinical studies impracticable.

The most widely available method for detection of rotavirus in stool is an enzyme immunoassay (EIA). Many EIA kits are commercially available. As these kits are easy to use, inexpensive, and rapid along with being highly sensitive, this is the diagnostic method used in most clinical laboratories. Latex agglutination is less sensitive and specific than EIA but is easy and rapid so is still used in some clinical laboratories. Other methods, including culture, PCR and electron microscopy, have been used to diagnose rotavirus but they are rarely available in the clinical setting.

Because norovirus cannot be cultured, reverse-transcription polymerase chain reaction (RT-PCR) of diarrheal stools or emesis is the diagnostic test of choice. Swabs of environmental samples also can be tested by RT-PCR and may help with containing an outbreak. RT-PCR is not available in many clinical laboratories but testing may be performed through the state public health laboratories. Enzyme linked immunosorbent assays (ELISA) are commercially available for the diagnosis of norovirus. The problem has been that the kits initially available had a low sensitivity, resulting in a large number of false negative tests. However, more recently developed kits have both improved sensitivity and specificity, making them useful in the clinical laboratory setting for diagnosis of norovirus.

EIAs are available for the diagnosis of astrovirus but are not widely available in clinical laboratories. More recently, RT-PCR has become available for the detection of astrovirus. The increased sensitivity of RT-PCR has nearly doubled the rate of detection of astrovirus among children with diarrhea. Thus, if EIAs are used to detect astrovirus, underestimation of the true prevalence of astrovirus infections is likely.

Enzyme immunoassays, the preferred method for the diagnosis of enteric adenovirus, are available commercially in many countries in the world but not the United States. Antigen detection, polymerase chain reaction assay, virus isolation, and serology also can be used to identify adenovirus infections. Since adenovirus can be excreted for prolonged periods, the presence of virus does not necessarily mean it is associated with disease.

Would imaging studies be helpful? If so, which ones?

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If you are able to confirm that the patient has viral gastroenteritis, what treatment should be initiated?

Oral rehydration solution (ORS) remains the mainstay of management for children with mild to moderate dehydration. Even when children have developed dehydration in excess of 10%, ORS still can be used to safely rehydrate the child. The main reason ORS is not used more commonly in the United States is that the method can be labor intensive. Parents and health care staff alike often state that the ORS is not working due to persistence of vomiting. This often can be alleviated by slow re-feeding of low volumes of ORS (sometimes as little as 15 ml over a few minutes) which frequently allows the stomach to absorb the liquid without vomiting. Volumes of ORS usually can be fairly rapidly increased after the vomiting stops, with children typically getting back to normal fluid intake within a day.

Ondansetron, a selective 5HT3 receptor antagonist, has been used for many years for the control of nausea and vomiting in patients undergoing chemotherapy. More recently, four randomized clinical trials have been conducted to test the ability of ondansetron to control vomiting in children with gastroenteritis. In each of the trials, administration of a single dose of ondansetron in the Emergency Department led to a 40%-65% decrease of children vomiting and a 50%-70% decrease of children requiring intravenous fluids compared with children receiving placebo. Limited data exist regarding repeated use of the medication during an acute episode and thus cannot be recommended at this time.

In the cases where ORT alone is not able to help the child, intravenous fluids, such as normal saline or ringer’s lactate, may be needed. In the setting of significant dehydration, manifested by orthostatic changes in blood pressure from the supine to sitting position, or poor skin turgor or sunken fontanel in young infants, rehydration needs to be initiated with rapid infusion of fluids. A bolus of 20 ml/kg (1 liter maximum) of isotonic fluid (normal saline or Ringer's lactate) should be given over 20 to 30 minutes and then the hydration status re-evaluated. It is unusual that more than 2 or 3 bolus infusions are needed to restore good perfusion. Measuring urine output, with a target of 1 mL/kg/hour, is an easy and reliable way to assess hydration status, assuming the child does not have kidney injury preventing urination. Upon completion of the bolus infusion, intravenous fluids should be changed to D5 ½ NS with potassium added (20 mEq/L) at 1.5 times maintenance rate. If ORS is tolerated, it is preferred to intravenous replacement as the method is very effective and can reduce the risk of fluid overload and alteration of the serum electrolytes.

As soon as the child is able to tolerate solid foods, it should be allowed. Early resumption of an unrestricted diet is now advocated by the American Academy of Pediatrics (AAP) and has been shown to more quickly resolve symptoms than previous prescribed restrictive diets. The use of probiotics, defined as oral supplements or food products that contain a sufficient number of viable microorganisms to alter the microflora of the host and offer the potential for beneficial health effects, for the treatment of gastroenteritis has been suggested by the AAP. When compared with placebo, probiotics have been associated with resolution of diarrhea about 1 day sooner. However, the effect has only been demonstrated significantly with rotavirus-associated diarrhea. Furthermore, as probiotics are considered food additives, standardization of doses and the organisms typed as probiotics are not well controlled, further adding to the difficulty in determining the utility of probiotics. While probiotics are unlikely to be deleterious, until further data are available on the most beneficial organism as well as the dose, frequency and duration of administration, routine use of probiotics for the treatment of gastroenteritis cannot be recommended.

A small study conducted in Egypt to treat diarrheal illness in children suggested that nitazoxanide (500 mg twice daily for 7 days) was effective for the treatment of norovirus. Because this outcome measure was only noted during sub-analysis and the effect was minor, shortening illness by 1 day (from 2.5 days to 1.5 days, placebo vs nitazoxanide), the results need to be confirmed before a recommendation to use the drug to treat norovirus can be made.

What are the adverse effects associated with each treatment option?

The main adverse event with fluid resuscitation is fluid overload. The only known adverse effect of probiotics are the rare cases of blood stream infections, principally in immunocompromised hosts, due to migration of the organism from the gut into the blood stream.

What are the possible outcomes of viral gastroenteritis?

Most children in developed countries will recover completely. Approximately 40 to 60 children per year in the United States die from viral gastroenteritis.

What causes this disease and how frequent is it?

Viral gastroenteritis is one of the most common infections in children in both the developed and developing world. Many viruses have been associated with gastroenteritis, but four—rotavirus, norovirus, enteric adenovirus, and astrovirus—cause the vast majority of disease. While most cases of viral gastroenteritis in the United States are mild, worldwide over 500,000 children die yearly from viral gastroenteritis, primarily due to rotavirus and norovirus.

Rotavirus

Rotavirus is characterized by two structural viral proteins (VP): VP4, the protease-cleaved protein (P protein) and VP7, the glycoprotein (G protein).Vaccine development has focused on the G and P proteins because they are important neutralizing antibody sites on the virus. The majority of disease is caused by G1, G2, G3 and G4 and, more recently, G9.

Norovirus

A member of the Calicivirus family, norovirus is a non-enveloped RNA virus consisting of a viral capsid and a nucleic acid core. Noroviruses can be divided into 5 genotypes (G-I through G-V) with G-I, G-II and G-IV being isolated from humans. The prototype of norovirus, called Norwalk virus, is a G-I type, but members of the G-II group currently are the most commonly circulating norovirus in the United States. This is important because immunity appears to have little to no heterotypic effect (i.e., G-I infection does not protect against G-II).

Astrovirus

Astroviruses are nonenveloped, single-stranded RNA viruses that are 28 nm in diameter and have a distinctive five or six pointed star pattern as seen by electron microscopy. There are eight known antigenic types of astrovirus. The virus has a worldwide distribution.

Enteric Adenovirus

Adenoviruses are non-enveloped viruses about 90-100 nm in size with an icosahedral shape seen by electron microscopy, and contain double-stranded DNA. There are at least 50 serotypes of adenovirus associated with human disease but only two, serotypes 40 and 41, cause gastroenteritis.

How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?

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How can viral gastroenteritis be prevented?

Good hygiene with frequent handwashing remains the primary mode of prevention of viral gastroenteritis. Because fresh fruits and vegetables purchased at the store may carry various organisms associated with enteric illness, including viral gastroenteritis, washing of these items prior to eating is another important measure. While alcohol-based hand sanitizer is adequate to disinfect hands against most agents associated with viral gastroenteritis, some evidence suggests that soap and water is superior to hand sanitizer for norovirus. Because agents causing viral gastroenteritis may survive on surfaces for days and may be resistant to killing, bleach at a concentration of 1000 parts per million is recommended to disinfect potentially contaminated surfaces.

At the current time, rotavirus is the only agent associated with viral gastroenteritis for which a vaccine is available. The goal of the rotavirus vaccine is to duplicate the protection produced by natural infection. Two vaccines are licensed for use in the United States. The US Food and Drug Administration (FDA) in 2006 approved the use of RotaTeq® (Merck and Company, Whitehouse Station, New Jersey), a live pentavalent vaccine containing a combination of human/bovine reassortant rotaviruses. The vaccine is given in a 3-dose series given at 2, 4 and 6 months of age. Rotarix® (produced by GlaxoSmithKline Biologicals, Rixensart, Belgium), a live-attenuated human rotavirus vaccine prepared from a single human strain (P1A_8_G1), was approved by the FDA in 2008. This vaccine is given as a two-dose series administered at 2 and 4 months.

Both vaccines have undergone extensive testing prior to licensure, with phase III trials in excess of 70,000 subjects in order to detect any signal for intussusception, an adverse event noted with a previous rotavirus vaccine. Both vaccines showed an efficacy of at least 95% in preventing serious disease and in excess of 70% efficacy for preventing rotaviral gastroenteritis of any severity.

No clinical trial has yet compared the efficacy of Rotarix® against that of RotaTeq®, and the Advisory Committee for Immunization Practices (ACIP) offers no vaccine preference. For both vaccines, the maximum age for dose 1 is 14 weeks and 6 days, and the maximum age for the last dose of rotavirus vaccine is 8 months.

Since licensing of the rotavirus vaccines, multiple studies have been conducted to determine vaccine effectiveness (VE). Similar to the results found in the clinical trials, VE has been found to be at least 80% for preventing infection. A recent report from the CDC funded New Vaccine Surveillance Network (NVSN) demonstrated VE of 95% against hospitalizations and visits to the Emergency Department with the effect lasting for at least 2 years after vaccination.